GPR6 is a member of the G protein-coupled receptor (GPCR) family of transmembrane receptors. GPR6 signals through the G protein (Gs) pathway. It is highly expressed in the central nervous system (CNS), particularly in medium spiny neurons (MSNs) of the striatum and exhibits minimal expression in peripheral tissues. The major striatal targets of dopaminergic innervation reside in the MSNs of the striatopallidal (indirect) and striatonigral (direct) output pathways. The MSNs of the direct output pathway express D1 dopamine receptors while those in the indirect pathway express D2 receptors. GPR6 is enriched in the D2 receptor-expressing MSNs of the striatum where GPR6 activity increases the levels of intracellular second messenger cAMP, which is functionally opposed to D2 receptor signaling. Antagonism or inverse agonism of Gs-coupled GPR6 decreases cAMP in MSNs and thus provides a functional alternative to dopamine-mediated activation of D2 receptors.
Published international patent application WO 2015/095728A1, which is hereby incorporated by reference in its entirety, describes a number of tetrahydropyridopyrazine derivatives, which are modulators of GPR6. These compounds include (S)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one (“Compound A”). Though Compound A is a potentially efficacious modulator of GPR6, it had a suboptimal safety margin relative to inhibition of hERG (human ether-a-go-go-related gene) activity. See e.g., X. Yao et al., British Journal of Pharmacology (2008) 154:1446-56. Inhibition of hERG is one factor associated with potential QT interval prolongation and cardiac arrhythmia.